No significant differences in recurrence rates among women with DCIS taking anastrozole or tamoxifen

SAN ANTONIO -- Postmenopausal women with ductal carcinoma in situ (DCIS) had similar outcomes with disease recurrence whether they took tamoxifen or the aromatase inhibitor anastrozole for five years after surgery, but women in the two groups had different side effects, according to results from the phase III IBIS-II DCIS clinical trial presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8-12.

This study is being published simultaneously in The Lancet.

"The IBIS-II DCIS study followed on from the ATAC and other aromatase inhibitor trials that showed aromatase inhibitors were more effective than tamoxifen in preventing recurrence of hormone receptor-positive invasive breast cancer in postmenopausal women," said Jack Cuzick, PhD, professor and director of Wolfson Institute of Preventive Medicine, Queen Mary University of London. "Given the paucity of data on the effect of aromatase inhibitors on DCIS, it was a natural step to explore them for women with DCIS.

"In this trial, we found that the women in both the anastrozole and tamoxifen groups had similar overall efficacy, with slightly better outcomes for those who took anastrozole. The side-effect profiles were very different for the two drugs; however, the patients had identical compliance and balancing side effects," Cuzick added.

"Anastrozole offers another choice for treating patients with estrogen receptor-positive DCIS. Choice may depend more on tolerability and existing conditions related to side effects than efficacy," he said.

In this multicenter, randomized, placebo-controlled trial, 2,980 postmenopausal women with locally excised hormone receptor-positive DCIS were enrolled; 1,471 were randomly assigned 1mg/day anastrozole and 1,509 were randomly assigned 20 mg/day tamoxifen. All women also received a placebo that looked like the test drug they did not receive in order to ensure that the side-effect profile assessments were reliable, Cuzick explained. The primary endpoint of the study was to assess breast cancer recurrence.

After a median follow-up of 7.2 years, 144 participants developed breast cancer, and 69 died, of which four were due to breast cancer. Women who took anastrozole had an 11 percent lower rate of recurrence of DCIS or invasive cancer than those who took tamoxifen, but this difference was not significant. There were no significant differences across subgroups except for invasive cancer recurrences: Women taking anastrozole were less likely to have HER2-negative invasive cancer recurrences, whereas women taking tamoxifen were less likely to have HER2-positive invasive cancer recurrences.

Side effects from the two drugs

Women who took anastrozole experienced fewer endometrial and ovarian cancers and skin cancers compared with those who took tamoxifen. However, more strokes were seen among those receiving anastrozole. Data were not sufficiently mature to assess differences in death rates.

Women who took tamoxifen had more major thromboembolic events and gynecological issues, including hot flashes, vaginal hemorrhage, and discharge, compared with those who took anastrozole. On the other hand, women who took anastrozole had more fractures, musculoskeletal issues, and vaginal dryness.

"We are continuing to follow up the patients in this trial," said Cuzick. "Analysis of molecular characteristics of the baseline cancers and those that develop on treatment is underway."

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This study was supported by Cancer Research UK, National Health and Medical Research Council Australia, Breast Cancer Research Fund, and AstraZeneca. Cuzick received research grants from and is an ad hoc speaker for AstraZeneca.

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The mission of the 2015 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit http://www.sabcs.org.

Background: Third generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone receptor positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone receptor (HR) positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole versus tamoxifen in postmenopausal women with HR positive DCIS.

Methods: A multi-centre randomised placebo-controlled trial of 1mg/day anastrozole vs. 20mg/day tamoxifen for five years was conducted in 2980 postmenopausal women with locally excised HR positive DCIS diagnosed between 2003 and 2009. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. Secondary endpoints included type of recurrence, breast cancer mortality, other cancers, cardiovascular disease, fractures, adverse events and non-breast cancer deaths. All analyses were done on an intention-to-treat basis and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals.

Results: Women were randomly assigned to receive either anastrozole (1mg/day, N = 1471) or tamoxifen (20mg/day, N = 1509). Median follow-up was 7.2 years (IQR 5.6-8.9) and 144 breast cancer recurrences have been recorded. No difference in overall recurrence was observed (67 anastrozole vs. 77 tamoxifen; HR=0.89 (0.64-1.23), P=0.5), based on a non-significant 20% reduction in invasive recurrence (37 vs. 47; HR=0.80 (0.52-1.24), P=0.3) and no difference for DCIS recurrence (29 vs. 30; HR=0.99 (0.60-1.65), P=0.9). A total of 69 deaths were recorded (33 vs. 36; HR=0.93 (0.58-1.50), P=0.8). Endometrial (1 v 11) and ovarian cancer (0 v 6) and non-melanoma skin cancer (8 v 19) were much less common with anastrozole, but gastrointestinal was more common (16 v 7), leading to no overall differences in other cancers. Significantly higher rates of fractures, joint related symptoms, and cerebrovascular accidents/strokes were seen with anastrozole and significantly higher rates of vasomotor and gynaecological symptoms (except vaginal dryness), and muscle spasms with tamoxifen. Five year compliance rates were 67.5% for both treatments.

Conclusions: No clear efficacy differences were seen between the two treatments, although the data supports a greater efficacy for anastrozole. Side effect profiles were different, but there was no clear overall advantage for either treatment. Anastrozole offers another treatment option for postmenopausal women with HR positive DCIS, which maybe be more appropriate for some women with contraindications for tamoxifen. Longer follow up will be necessary to fully evaluate treatment differences.

This research will be presented at a press conference at the 2015 San Antonio Breast Cancer Symposium, moderated by SABCS Co-director Kent Osborne, MD, director of the Dan L Duncan Cancer Center at Baylor College of Medicine, Friday, Dec. 11, 7:30 a.m. CT in Room 217D of the Henry B. Gonzalez Convention Center. Reporters who cannot attend the press conference in person can call in using the following information:

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